The development of antimicrobial agents led to a significant decrease in morbidity and mortality from infectious diseases in this century. This accomplishment was largely due to the widespread use of the major classes of antibiotics, such as the sulfonamides, penicillins, cephalosporins, aminoglycosides, and tetracyclines (see, e.g., Goodman et al. (1995) The Pharmacological Basis of Therapeutics, Macmillan Publishing, New York). However, in recent years, the trend in reducing infectious disease mortality has been threatened by the emergence of resistant strains of microorganisms that are no longer susceptible to the currently available antimicrobial agents.
With the rise of antibiotic-resistant pathogens and infectious diseases, the need for new antimicrobial agents is urgent (see, e.g., Cohen et al. (1992) Science 257: 1050-1055). For example, the incidence of community-acquired and nosocomially acquired infections due to the bacterium Staphylococcus aureus is rising (Lowy (1998) N. Engl. J. Med. 339: 520-532.). From 1990 to 1992, this microorganism was the most common cause of nosocomial pneumonias and surgical wound infections (Emori and Gaynes (1993) Clin. Microbiol. Rev. 23: 255-259). The overall growing crisis in antibiotic resistance and the rise in the incidence of methicillin-resistant S. aureus (MRSA) strains (Schwarz et al. (1981) Mol. Gen. Genet. 183:181-186; Sista et al. (2004) Anesthesiol. Clin. N. Am. 22: 405-435.) have emphasized the need for therapeutic alternatives to currently available antibiotics. Vancomycin remains the mainstay of therapy against several resistant gram-positive pathogens. However, vancomycin is slowly bactericidal, and with the recent increase in nosocomial infections caused by vancomycin-resistant enterococci and S. aureus (Centers for Disease Control and Prevention (2002) Morbid. Mortal. Wkly. Rep. 51: 565-567; Diekema et al. (2004) Clin. Infect. Dis. 38: 78-85; Fujimura et al. (2004) J. Infect. Chemother., 10: 131-132), there is a growing need for antimicrobial agents with novel mechanisms of action to attack these resistant pathogens.
Biologically active peptides, such as antimicrobial peptides (hereinafter “AMPs”), are believed to be less likely to develop resistance because the antimicrobial peptides show activity by mechanisms that are totally different from that of conventional antibiotics.
Typically AMPs are low molecular weight peptides that exhibit antimicrobial activity. Naturally-occurring AMPs are part of the innate immune response of plants, invertebrates and vertebrates. AMPs include, among others, cecropins (see, e.g., Hultmark et al. (1980) Eur. J. Biochem., 106: 7-16; Hultmark et al. (1982) Eur. J. Biochem., 127: 207-217), apidaecins (see, e.g., Casteels et al. (1989) EMBO J. 8: 2387-2391), magainins (see, e.g., Zasloff (1987) Proc. Natl. Acad. Sci., USA, 84: 5449-5453; Zasloff et al. (1988) Proc. Natl. Acad. Sci., USA, 85: 910-913), tachyplesins and analogues of tachyplesins such as polyphemusins (see, e.g., Nakamura et al. (1988) J. Biol. Chem. 263: 16709-16713; Miyata et al. (1989) J. Biochem., 106: 663-668), defensins (Lehrer et al. (1991) Cell 64: 229-230; Lehrer et al. (1993) Ann. Rev. Immunol., 11: 105-128; U.S. Pat. Nos. 4,705,777; 4,659,692; 4,543,252), β-defensins (see, e.g., Selsted et al. (1993) J. Biol. Chem., 288: 6641-6648; Diamond et al. (1991) Proc. Natl. Acad. Sci., USA, 88: 3952-3958), insect defensins (see, e.g., Lambert et al. (1989) Proc. Natl. Acad. Sci., USA, 88: 262-265; Matsuyama and Natori (1988) J. Biol. Chem., 263: 17112-17116), and protegrins (see, e.g., Kokryakov et al. (1993) FEBS 337: 231-236; Zhao et al. (1994) FEBS Lett. 346: 285-288; Migorodskaya et al. (1993) FEBS 330: 339-342; Storici et al. (1993) Biochem. Biophys. Res. Commun., 196: 1363-1367; Zhao et al. (1994) FEBS Lett. 346: 285-288; Manzoni et al. (1996) FEBS Lett. 383: 93-98; U.S. Pat. No. 5,464,823). The discovery of these new classes of antimicrobial peptides offers hope that some might be developed into agents that can be used against microorganisms of medicinal importance.
At least one antimicrobial peptide, daptomycin, a cyclic lipodepsipeptide antibiotic, has been approved for the treatment of complicated skin and skin structure infections caused by several gram-positive bacteria. Its mode of action appears to be related to the disruption of the membrane potential of the bacterium, which is caused by the favored oligomerization of daptomycin upon extracellular calcium binding (Jeu and Fung (2004) Clin. Ther. 26: 1728-1757).